EBF Tiered approach final. Validation criteria. Philip Timmerman, on behalf of the EBF 8 th EBF Open Symposium

Transcription

1 EBF Tiered approach final recommendation of Scientific Validation criteria Philip Timmerman, on behalf of the EBF 8 th EBF Open Symposium

2 The problem statement 1990 CC-I 2001 FDA Further refinement, maybe overdesign of requirements for BA/BE studies via 483 or CC-conference papers p Many new formats, technologies and analytical requests in earlier phases for which applying Guidance is challenging htt-sp:// 2

3 Tiered approach 1 st appearance Formally introduced in CC-III (2006) in relation to metabolites in early developmen <<Characterization of UMMs should proceed using a flexible, tiered approach to bioanalytical methods validation. This tiered approach would allow metabolite screening studies to be performed in early drug development using bioanalytical methods with limited validation, with validation criteria increasing as a product moves into clinical trials. A tiered validation approach to metabolite determination would defer bioanalytical resource allocation to later in the drug development timeline when there is a greater likelihood of drug success. As a minimum, the specifics of this tiered validation process should be driven by scientifically appropriate criteria, established a priori >> Workshop/Conference Report Quantitative Bioanalytical Methods Validation and Implementation: Best Practices for Chromatographic and Ligand Binding Assays. CT Viswanathan et al., AAPS J Mar; 9(1): E30 E42 htt-sp:// 3

4 Tiered approach 1 st appearance No clear definition or further context was given on waiver As a stand alone paragraph, it was not ready for use as alternative approach, and hence not embraced Increased pressure of 483s/new Guidelines (EMA/Anvisa/ ) took priority in BA community since 2010 htt-sp:// 4

5 So.Tiered approach? htt-sp:// 5

6 Still Early 2009 A Tiered Approach team was established in EBF Team members: Achim Freisleben (Merck), Ben Gordon (Servier), Morten Kall (Lundbeck), Philip Timmerman (JnJ), Richard Hucker (Pfizer), Sirpa Laakso (Orion) Survey on key elements of qualified assays issued EBF identified 3 tiers of quality: S-Q-V 34 questions translating method validation criteria into refined criteria for qualified assays Plans to refine and publish in 2010 htt-sp:// 6

7 AAPS Annual Meeting 2009 FB from EBF on their efforts to further develop the principles of tiered approach as guidance principle for many studies, with initial focus on MIST Presentation ti by Brian Booth on reflections to refine tiered approach into Low/Medium/High validations htt-sp:// 7

8 But Late 2009: Discussions refocussed on ICH M3 (R2) Team decided to publish on metabolite quantification first: Ref: Best practices in a tiered approach to metabolite quantification: views and recommendations of the European Bioanalysis Forum. Bioanalysis, July 2010, Vol. 2, No. 7, Pages Mid 2010: GBC formed A2 tiered approach identified as team EBF decided to postpone further publication plans and feed current results of EBF discussion into GBC htt-sp:// 8

9 , Overcoming the hurdles: building, brick by brick Industry: Refinement of semantics of qualified/research/non-validated nomenclature into scientific validation/regulatory l t validation Ref. Tiered Approach revisited: introducing Stage-Appropriate or Assay- Appropriate Scientific Validation, Bioanalysis, Vol. 6, No. 5, Pages Frequently challenging the value of regulatory validation as checkbox for all studies. Identified areas where alternative approaches can be proposed Took a fresh look at how existing regulations should or should not impact day-to-day practice (GLP, ICH, GCP, CSV,..) Health Authorities Seem to be supporting the evolution htt-sp:// 9

10 From pie in the sky into practice - 1 Until 2014, discussion was mainly focussed in EU and in BA community only Action Actively engage other regions Joint DV-DMDG meeting Jan 2015 Discussion at JBF March 2015 CPSA China April 2015 Initiated t contact t with ICH Q1/ Reach out to other stakeholders Get perspective from QA, ClinPK, Toxicology (@ CPSA US, 2015) Seek FB from regulators (@ EBF-2014 (David Jones, AAPS Open Forum 2015 FB Faye, next presentation) htt-sp:// 10

11 From pie in the sky into practice - 2 Identify what is still missing for the BA community Manage fear Show successes Provide better tools to share the added value and the details of TA (in the mean time re-worded into Scientific validation) with stakeholders o Clear criteria 2015 EBF Recommendation next pages o Define areas of application (..as a way to define areas on non-application) 5 proposed areas Tissue Urine Metabolites Early non pivotal GLP Early non pivotal Clinical htt-sp:// 11

12 A value proposition Can Industry /HA agree on an alternative approach for validation of assays in support of non-pivotal studies in early development. At all times concentration data generated should be in scientific compliance with key bioanalytical quality criteria: documented evidence of accuracy, precision, selectivity, sensitivity, stability and reproducibility of the bioanalytical method to make the right decision in a study/project no cutting corners Allow scientific freedom to answer the questions asked Facilitates retrospective review of data quality to support other decisions if so required later in development htt-sp:// 12

13 EBF recommendation Reference: Tiered approach into practice - scientific validation for chromatography-based assays in early development: a recommendation from the European Bioanalysis Forum. Bioanalysis, Vol. 7, No. 18, Pages htt-sp:// 13

14 The focus of the recommendation Pre-GLP GLP POC Post POC Screening/qualified accepted best practice Scientific validation Validation (or Regulatory Validation ) accepted best practices htt-sp:// 14

15 Being aware.. Pre-GLP GLP POC Post POC Screening/qualified accepted best practice Area of V lid ti ( ambiguity and d/ or fear Validation (or Regulatory Validation ) accepted best practices Not all in industry are convinced of added value of scientific validation. Some are convinced but not supported by their environment. Their main concerns: fear for 483, more FB in AAPS/EBF/JBF survey Are we really saving resources? see teaser htt-sp:// 15

16 EBF recommendation - areas Five areas where applying scientific validation can be or has proven to be a valid alternative for regulatory validation. 1. All Urine analysis clinical/preclinical 2. All tissue homogenate analysis 3. All metabolites analysis prior to decision which metabolites require continued quantification using regulatory validation based on ICH(M3) and EMA-DDI: 4. A selection of non-pivotal ED clinical studies: focus on phase 0 and First into Man 5. All (Non pivotal) Early GLP studies: principles of scientific validation are compatible with GLP regulations htt-sp:// 16

17 Recommended approach Not built on loose sand: Builds on 25 y of experience with Guideline criteria Refines them to the right balance of scientific requirements, scientific freedom and resource requirements htt-sp:// 17

18 Recommended approach Tries to integrate discussions from many in industry Proposes clear, recognizable and refined criteria based on key elements of bioanalytical quality for harmonized day-to-day application. Focuses on the scientific challenge of study. Allows better use of resources, both in the execution and reporting Can withstand scientific scrutiny and regulatory review if needed d Facilitates retrospective review of data quality to support other decisions than intended if so required later in development htt-sp:// 18

19 In a Nut Shell Scientific Validation Single run pre-study validation when it makes sense to do so Consider in-study validation for certain elements (e.g. stability, dilution integrity) Combine stability experiments to simplify Wider P&A criteria may be appropriate for the end point decision (e.g. 20%/25%) Increased focus on in-study study performance Exclude experiments that make no scientific sense (based on industry experience...) extensive selectivity (incl. haemolysed/lipemic) ) co-meds, OTCs, FDC testingti Recovery Replicates of pre-study matrix, LLOQ, ULOQ testing htt-sp:// 19

20 How does it work Pre-study acceptance criteria i In-study acceptance criteria i htt-sp:// 20

21 In detail: pre- study validation Metabolites in plasma (ICH M3) Urine Tissue homogenates Early development clinical studies Early development preclinical studies Guideline dl assay appropriate scientific validation ld stage appropriate scientific validation CoA with at minimum proofof of y N Y or use dosed batch identity/purity Calibration curve: number of calibration samples Acceptance criteria CAL Minimum 6, covering range Minimum 6, covering range Minimum i 5, covering range incurred samples incurred incurred samples samples 75% and at 75% and at least 5 points least 5 points within 15% within 20% LLOQ) LLOQ) 75% and at least 5 points within 25% LLOQ 75% and at least 6 points within 20% LLOQ) Matrix QC identical as study y Y Y (or matrix matching) Y QC levels replicates 4 (LLOQ/low/mi d/high) min. 5 reps 3 (low/mid/high) min 3 reps 4 (LLOQ/low/mid/high) min. 5 reps htt-sp:// 21

22 In detail: pre- study validation Metabolites in plasma (ICH M3) Urine Tissue homogenates Early development clinical studies Early development preclinical studies Guideline assay appropriate scientific validation stage appropriate scientific validation Acceptance criteria QC mean bias 20% 20% 25% 20% (25% at LLOQ) Acceptance criteria QC (%CV per level) 15% (20% at LLOQ) 20% 25% 20% (25% at LLOQ) Inter assay variability 15% Use scientific judgment based upon P&A of 1 Use scientific judgment based run validation upon P&A of 1 run validation QC/Cal from separate stocks N N Y (unless check equivalence) Y, unless accuracy of stock proven Selectivity 6 Min. one source of blank matrix (as used for cals/qcs) multiple sources depending di on practicality 6 n=1 matrix source is still relevant htt-sp:// 22

23 In detail: pre- study validation Metabolites in plasma (ICH M3) Urine Early Tissue homogenates development clinical studies Early development preclinical studies Guideline assay appropriate p scientific validation stage appropriate scientific validation Extraction recovery N N Carryover Y In study Matrix effect Y N, assess within study runs via IS response Dilution integrity it Y In study LLOQ As defined by acceptable LLOQ CAL As defined by acceptable LLOQ CAL standard standard Comed selectivity (in support of DDI Y N studies) Over the Counter (OTC) stability Fixed Dose Combination stability N anticipated N N htt-sp:// 23

24 In detail: pre- study validation Metabolites in plasma (ICH M3) Urine Early Tissue homogenates development clinical studies Early development preclinical studies Guideline assay appropriate scientific validation stage appropriate scientific validation Processed sample stability/reproducibi Y N scientific judgment lity Stock solution 20% minimal Y, unless prepared the same Y If available previously stability assessment day. Bench top stability Y N Sample stability for duration of storage Y Y (20%) N F/T stability Y (3 cycles) N, consider ISS Y (1 cycle) Y, consider Y, Specify Sampling conditions Y N including conditions, container and consider EBF adsorption paper Consider combined stability experiment to cover unknown samples htt-sp:// 24

25 In detail: pre- study validation Metabolites in plasma (ICH M3) Urine Early Tissue homogenates development clinical studies Early development preclinical studies Guideline assay appropriate scientific validation stage appropriate scientific validation i Whole blood stability N N, unless for known problem scaffolds n/a N, unless for known problem scaffolds [22] Hemolytic N (Y, EMA) N n/a N Hyperlipidemic N (Y, EMA) N n/a N Validation Y (SOP or at minimum SOP or short protocol summarizing scientific parameters to plan/protocol protocol) be tested Validation report Y(Extensive) At minimum a document summarizing scientific parameters tested Misc. Consider longer run time instead of specificity experiment # = during meth dev. Non Specific Calibration Binding / matrix may be sampling a surrogate conditions & aliquoting htt-sp:// 25

26 In detail: in-study acceptance criteria Metabolites in plasma (ICH M3) Urine Tissue homogenates Early development clinical studies Early development preclinical studies Guideline Calibration curve: Minimum i 6, number of covering the calibration ranges of samples incurred samples Acceptance criteria CAL 75% and at least 6 points within 15% LLOQ) assay appropriate scientific validation Minimum 5, covering the ranges of incurred samples 75% and at least 5 points within 20% LLOQ) 75% and at least 5 points within 25% LLOQ) stage appropriate scientific validation Minimum 6, covering the ranges of incurred samples 75% and at least 6 points within 20% LLOQ) Inter assay variability Matrix CAL/QC identical as study Y Use scientific judgment Y Y Y (or matrix matching) Y Number of QC levels/replicates 5%, at least 3 (low/mid/high) 2 reps 3 (low/mid/high) 2 reps htt-sp:// 26

27 In detail: in-study acceptance criteria Early Metabolites in Early Tissue plasma (ICH Urine homogenates development development preclinical M3) clinical studies studies Guideline assay appropriate scientific validation stage appropriate scientific validation , ½ of QC run , ½ of QC , ½ of QC samples per , ½ of QC samples per QC samples acceptance (bias) samples per level level level per level Acceptance criteria QC mean bias (for 15% 20% 25% 20% n>1 batch study sizes) ISR EMA paper N Y, once Y, once per species Carry over Y Y, Assess impact Dilution integrity (may be QC) Y If required IS variability with criteria Y Scientific judgment Refer to EBF paper N, is part of IS tracking, Hemolytic N (Y, EMA) N n/a interrogate anomalous results observation recorded by clinical Unit htt-sp:// 27

28 In detail: in-study acceptance criteria Metabolites in plasma (ICH M3) Urine Early Tissue homogenates development clinical studies Early development preclinical studies Guideline assay appropriate scientific validation stage appropriate scientific validation Hyperlipidemic N (Y, EMA) N n/a Anomalous result repeats Extrapolation beyond curve Misc. Repeat ifdrug in placebo/control N, is part of IS tracking Y N Yes, as requested in duplicate N Y scientifically based extrapolation justified Selectivity by dilution of incurred samples Protocol & report QA d if claiming GLP n/a Yes in duplicate In-study validation as part of study sample analysis: if only in-study validation is performed (no pre-validation), include (with predefine acceptance criteria) those relevant missing parameters from scientific validation above mentioned (e.g. relevant stability) htt-sp:// 28

29 Documentation/reporting Keep it brief and relevant Include reference to Study Number, Protocol or SOP signed by sponsor??? Template scope of scientific validation to frame the context maybe with reference to EBF recommendation paper or other? Body: (reference to) assay description short summary table providing evidence of assay performance, range and stability More detail in appendix as required or as per company desire (e.g. sponsor-vendor relationship) No need to include chromatograms No GLP claim on validation Signature of study responsible person htt-sp:// 29

30 Finally vs Is the anxiety around more liberal l acceptance criteria a valid worry or are we over-reacting? For SMOL BA current practice = , but most studies come better acc&prec. In practice, also with more liberal criteria, most studies will be coming in at better acc&prec, than , and likely even Having more pre-agreed liberal acceptance criteria, will prevent undue repeat for those studies which fall outside (too) stringent criteria for the purpose of the study htt-sp:// 30

31 A teaser Why all this effort for my study? Once my compound progresses, I need to redo the validation. So, I am doubling my workload htt-sp:// 31

32 Let s make the math for what s is worth Using the attrition rate reported by the Tufts CSDD 2014 model, refined to match BA-attrition: preglp 250 compounds GLP 25 compounds FIM 12 compounds > MIST 5 compounds POC 2 compounds > POC 1 compound Current approach: To get 1 compound to the market we need 3720 validation days* 319 regulatory validations Alternative approach To get 1 compound to the market we need 1393 validation days* 29 regulatory validations 209 scientific validations * assumptions: 12/5 days for RV/SV, 1 metabolite/project from GLP onwards htt-sp:// 32

33 Active Metabolite Urine Tissue Cpds # RV #SV RDMRaH RDMRaH RDMRaH RDMRaH preglp 250 GLP FIM > MIST POC > POC Active Metabolite Urine Tissue Cpds # RV #SV RDMRaH RDMRaH RDMRaH RDMRaH preglp 250 GLP FIM > MIST POC > POC assumption attrition rate cfr. Tufts model CSDD 2014 model 1 Regulatory full validation = 12 days 1 scientific validation = 5 days for plasma/urine/tissue/metabolites htt-sp:// 33

34 Next steps Recommendation can serve as a toolbox for the bioanalyst It is not intended as an endpoint of the discussion. E.g. the CC-I, II, III,. were no endpoints either. As science progresses and experience builds, proposals can be a step stone for future refinements Continued need for intensified global discussion and feedback from the regulatory agencies: A cross-regionalregional team (EBF, AAPS/IQ, JBF) is being formed to take the discussion further consideration an EBF/AAPS/JBF organized CC-VII type meeting Further discussions on how to approach ICH htt-sp:// 34

35 Panel discussion Clinical & Pharmaceutical Solutions through Analysis October 5-8, 2015 Sheraton Bucks County Hotel, Langhorne, PA Where Technology and Solutions Meet! Questions to focus on: 1. What is needed d to further implement scientific validation in the areas proposed? 2. Are there other areas where the principles of tiered approach add value? htt-sp:// 35

36 Rome wasn t built in a day, but they built it. after John Heywood htt-sp:// 36

37 Acknowledgements Many friends and colleagues in industry, with special thanks to AAPS BFG DV-DMDG CPSA EBF GBC JBF htt-sp:// 37

38 Publications 1. Fit-for-Purpose Method Development and Validation for Successful Biomarker Measurement, Pharmaceutical Research Vol. 23, No. 2, Feb 2006, Workshop/Conference Report Quantitative Bioanalytical Methods Validation and Implementation: Best Practices for Chromatographic and Ligand Binding Assays. The AAPS Journal 2007; 9 (1) 3. Bringing new technologies into regulatory space. Bioanalysis, Vol. 4, No. 23, Pages Managing scientific, technical and regulatory innovation in regulated bioanalysis: a discussion paper from the European Bioanalysis Forum. Bioanalysis, Jan 2013, Vol. 5, No. 2, Pages When do you need a validated assay? Bioanalysis, Vol. 3, No. 24, Pages Generic approach to validation of small-molecule LC-MS/MS biomarker assays Bioanalysis Nov;1(8): Best practices in a tiered approach to metabolite quantification: views and recommendations of the European Bioanalysis Forum. Bioanalysis, July 2010, Vol. 2, No. 7, Pages European Bioanalysis Forum recommendation: scientific validation of quantification by accelerator mass spectrometry.. Bioanalysis, Nov 2012, Vol. 4, No. 22, Pages Bioanalysis for plasma protein binding studies in drug discovery and drug development: views and recommendations of the European Bioanalysis Forum. Bioanalysis Mar;6(5): Recommendations from the European Bioanalysis Forum on method establishment for tissue homogenates. Bioanalysis, Vol. 6, No. 12, Pages Tiered Approaches to Chromatographic Bioanalytical Method Performance Evaluation: Recommendation for Best Practices and Harmonization from the Global Bioanalysis Consortium Harmonization Team. AAPS Journal, January 2015, Volume 17, Issue 1, pp Reflecting on a decade of metabolite screening and monitoring. Bioanalysis, Vol. 6, No. 5, Pages Measuring soluble biomarkers in clinical trials: do tiered approaches to the analysis and validation of assays provide an answer to the fit-for-purpose challenge? Bioanalysis, Vol. 6, No. 5, Pages Feedback from the European Bioanalysis Forum Workshop: Taking tiered approach to the next level. Bioanalysis. Vol. 6, No. 19, Pages Timmerman P. Tiered Approach revisited: introducing Stage-Appropriate or Assay-Appropriate Scientific Validation, Bioanalysis, Vol. 6, No. 5, Pages Scientific or regulated validation: a tiered approach? Meeting report from a joint EBF/DVDMDG workshop. Bioanalysis 7:14, Tiered approach into practice - scientific validation for chromatography-based assays in early development: a recommendation from the European Bioanalysis Forum. Bioanalysis, Vol 7 htt-sp:// 38